Pre-synaptic Cav2.2 (N-type) voltage-gated calcium channels in the dorsal horn of the spinal cord modulate the release of key pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP), indicating the potential therapeutic use of Cav2.2 calcium channel blockers as analgesics.
Peptidic ω-conotoxins, isolated from the venom of cone snails, have been shown to be selective for Cav2.2 calcium channels and can block SP release in the spinal cord (Smith at al. (2002) Pain, 96: 119-127). Moreover, they have been shown to be antinociceptive in animal models of chronic pain following intrathecal administration (Bowersox at al. (1996) Journal of Pharmacology and Experimental Therapeutics, 279: 1243-1249; Smith et al. (2002) supra), and have been shown to be effective analgesics in clinical use, particularly in the treatment of neuropathic pain (Brose et al. (1997) Clinical Journal of Pain, 13: 256-259).
Winquist et al. has shown that Cav2.2 channels may offer the potential to reduce neuronal signalling, thereby treating disorders such as pain. However, side effect issues may impact the success of such an approach (Winquist et al. (2005) Biochemical Pharmacology, 70: 489-499). A number of journal articles have been published on the effect of natural inhibitors of Cav2.2 channels (see Bowersox et al. (1996) Journal of Pharmacology and Experimental Therapeutics 279(3):1243-1249; Scott et al. (2002) European Journal of Pharmacology 451(3):279-286). In addition, several journal articles have been published on the phenotypic characterisation of transgenic mice lacking the Cav2.2 gene (see Saegusa et al. (2001) EMBO J. 20(10):2349-2356; Kim et al. (2001) Mol. Cell. Neurosci. 18(2):235-245). These articles support the stance that tonic inhibition of Cav2.2 may result in cardiovascular (hypotension) and CNS (sedation) side effects at therapeutic concentrations.
Due to these drawbacks of tonic Cav2.2 inhibitors, it is the object of the invention to provide an alternative class of Cav2.2 antagonist: a state- or use-dependent Cav2.2 blocker, which has the potential to selectively inhibit highly active channels contributing to the pathophysiology of chronic pain whilst sparing the contributions of Cav2.2 to wider physiological levels of activity within the peripheral and central nervous system. Therefore, one object of the invention is to identify novel compounds for use in therapy that block Cav2.2 calcium channels under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes.
Recent studies also provide evidence for a contribution of T-type calcium channels to the pathophysiology of acute (nociceptive) and chronic pain. T-type channels exist as three distinct subtypes, namely Cav3.1-3.3, which differ in their expression and functional properties. All three subtypes are expressed in DRG neurones where their knockdown with anti-sense approaches has highlighted the role in particular of Cav3.2 to chronic pain (Bourinet et al (2005) EMBO J. 24:315-24). Further studies have indicated that these channels are functionally up-regulated in the rat streptozotocin model of diabetic neuropathy (Messinger et al (2009) Pain. 145:184-95) and in genetically obesity prone Ob/Ob mice (Latham et al (2009) Diabetes 58:2656-65) where they contribute to the measured hyperalgesia. Consequently, T-type calcium channel (Cav3.2) inhibitors may have therapeutic applications in the treatment of pain. Furthermore, as already discussed for the N-type calcium channels (Cav2.2), inhibitors which possess a use-dependent mechanism of action may be expected to show an optimum balance between efficacy and side effects. Thus, specifically targeting both N- and T-calcium channel types with the same inhibitor acting as a use-dependent antagonist has the potential to simultaneously inhibit multiple points of the signalling pathway which contribute to the conscious perception of pain. This has the potential to deliver additive or synergistic effects which may lead to increased efficacy as manifested in a greater magnitude of response and/or a greater responder rate to treatment in a diverse population of patients with chronic pain syndromes. A therapeutic benefit may also be achieved with a better tolerability profile as a result of this improved efficacy.
Therefore, it is a further object of the invention to identify novel compounds for use in therapy that preferentially block Cav2.2 and Cav3.2 calcium channels under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes.
WO 2008/024284 (Merck & Co) describes a series of sulfonylated piperazines as cannabinoid-1 (CB1) receptor modulators which are claimed to be useful in the treatment for example of psychosis, cognitive disorders and Alzheimer's disease. WO 96/31501 (Schering Corporation) describes carbonyl-piperazinyl and piperidinyl compounds which inhibit farnesyl protein transferase. WO 2005/113542 (Elan Pharmaceuticals) describes N-cyclic sulfonamido compounds which inhibit gamma secretase and beta-amyloid peptide release and/or its synthesis.